Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy (METIV-HCC)

A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy

The purpose of this study is to determine if tivantinib (ARQ 197) is effective in treating patients with MET diagnostic-high hepatocellular carcinoma (liver cancer) who have already been treated once with another therapy.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Placebo; Drug: Tivantinib

Detailed Description

Expression of c-Met in tumors correlates with aggressive hepatocellular carcinoma (HCC) features. Overexpression of the receptor in tumor samples or high level of blood HGF in subjects is related to higher recurrence rate after surgery for HCC, while high c-Met expression correlates with shorter survival in HCC subjects. In summary, c-Met holds an important prognostic role in the natural history of HCC. This Phase 3 study in MET Diagnostic-High inoperable HCC subjects has been designed based on the results from the randomized, controlled Phase 2 study conducted by ArQule, Inc. with tivantinib versus placebo in subjects with MET Diagnostic-High inoperable HCC who have failed one prior systemic therapy, mentioned above. The purpose of this study is to confirm the efficacy of tivantinib in MET Diagnostic-High HCC subjects who were previously treated with one systemic therapy, and to further evaluate the safety profile of the experimental drug in this subject population.

• Study Type: Interventional
• Enrollment (Actual): 383
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Pilar, Argentina
  • Buenos Aires
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
  • Caba
    • Buenos Aires, Caba, Argentina
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
  • Victoria
    • Heidelberg, Victoria, Australia
    • Melbourne, Victoria, Australia
  • Western Australia
    • Nedlands, Western Australia, Australia
• Austria
  • Graz, Austria
  • Innsbruck, Austria
  • Linz, Austria
  • Wien, Austria
• Belgium
  • Brussels, Belgium
  • Ghent, Belgium
  • Leuven, Belgium
  • Liege, Belgium
• Brazil
  • Barretos, Brazil
  • Rio de Janeiro, Brazil
  • RS
    • Porto Alegre, RS, Brazil
  • SP
    • Sao Paulo, SP, Brazil
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Toronto, Ontario, Canada
• France
  • Amiens Cedex 1, France
  • Bordeaux Cedex, France
  • Caen Cedex 09, France
  • Clichy, France
  • Creteil, France
  • Grenoble, France
  • Lille Cedex, France
  • Marseille Cedex 09, France
  • Montpellier, France
  • Paris Cedex, France
  • Paris Cedex 12, France
  • Reims Cedex, France
  • Rennes Cedex, France
  • Toulouse Cedex 09, France
  • Villejuif Cedex, France
• Germany
  • Aachen, Germany
  • Berlin, Germany
  • Bonn, Germany
  • Duesseldorf, Germany
  • Essen, Germany
  • Frankfurt am Main, Germany
  • Hamburg, Germany
  • Hannover, Germany
  • Heidelberg, Germany
  • Leipzig, Germany
  • Magdeburg, Germany
  • Mainz, Germany
  • Muenchen, Germany
  • Munich, Germany
  • Regensburg, Germany
  • Tuebingen, Germany
  • Ulm, Germany
  • Wuerzburg, Germany
• Italy
  • Benevento, Italy, 82100
  • Bergamo, Italy
  • Bologna, Italy
  • Catania, Italy
  • Firenze, Italy
  • Milano, Italy
  • Modena, Italy
  • Napoli, Italy
  • Padova, Italy
  • Parma, Italy
  • Pavia, Italy
  • Pisa, Italy
  • Reggio Emilia, Italy
  • Roma, Italy
  • Turin, Italy
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy
  • Milano
    • Rozzano, Milano, Italy
  • Torino
    • Orbassano (TO), Torino, Italy
• Netherlands
  • Amsterdam, Netherlands
• New Zealand
  • Auckland, New Zealand
• Portugal
  • Lisboa, Portugal
  • Porto, Portugal
  • Vila Real, Portugal
• Spain
  • Alicante, Spain
  • Barcelona, Spain
  • Cordoba, Spain
  • Madrid, Spain
  • Sabadell, Spain
  • Santander, Spain
  • Valencia, Spain
  • Zaragoza, Spain
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain
  • Asturias
    • Oviedo, Asturias, Spain
  • Madrid
    • Majadahonda, Madrid, Spain
  • Navarra
    • Pamplona, Navarra, Spain
• Sweden
  • Gothenburg, Sweden
  • Stockholm, Sweden
• Switzerland
  • Bern, Switzerland
  • Zurich, Switzerland
• United States
  • Arizona
    • Tucson, Arizona, United States
  • California
    • Los Angeles, California, United States
    • Orange, California, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Gainesville, Florida, United States
  • Illinois
    • Chicago, Illinois, United States
  • Kansas
    • Westwood, Kansas, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Maine
    • Scarborough, Maine, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Detroit, Michigan, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
  • New Jersey
    • Hackensack, New Jersey, United States
  • New York
    • New York, New York, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Texas
    • Dallas, Texas, United States
    • Galveston, Texas, United States
    • Houston, Texas, United States
  • Washington
    • Seattle, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed HCC that is inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), and not eligible for local therapy
• MET Diagnostic-High tissue reported by the central authorized laboratory using archival or recent biopsy tumor samples
• Received at least 4 weeks of one prior sorafenib containing systemic therapy and then experienced documented radiographic disease progression; or inability to tolerate prior therapy received for at least a minimum period of time.
• Discontinued prior systemic treatment or any investigational drug for at least 2 weeks (14 days) or for at least 3 weeks for IV anti-cancer drugs, prior to the study randomization
• Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed >= 4 weeks prior to randomization
• Measurable disease as defined by the RECIST v1.1.

Exclusion Criteria:

• More than 1 prior systemic regimen (prior MET inhibitors/antibodies are not allowed; experimental systemic therapy for inoperable HCC given before or after sorafenib counts as separate regimen and is not allowed)
• Child-Pugh B-C cirrhotic status based on clinical findings and laboratory results
• Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors. Any cancer curatively treated more than 3 years prior to enrollment is permitted.
• History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as greater than or equal to Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring more than 6 months prior to study entry is permitted)
• Active clinically serious infections defined as >= Grade 3 according to NCI CTCAE
• Any medical, psychological, or social conditions, particularly if unstable, including substance abuse, that may, in the opinion of the Investigator, interfere with the subject's safety or participation in the study, protocol compliance, or evaluation of the study results
• Known human immunodeficiency virus (HIV) infection
• Blood or albumin transfusion within 5 days prior to the blood draw being used to confirm eligibility
• Concomitant interferon therapy or therapies for active Hepatitis C virus (HCV) infection
• Pregnancy or breast-feeding
• History of liver transplant
• Inability to swallow oral medications
• Clinically significant gastrointestinal bleeding occurring <= 4 weeks prior to randomization
• Pleural effusion or clinically evident (visible or palpable) ascites

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tivantinib 240 mg BID Cohort; The tivantinib dosage of 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Drug: Tivantinib; Tivantinib tablets; Other Names: ARQ197
Experimental: Tivantinib 120 mg BID Cohort; Tivantinib 120 mg is administered by oral tablet BID, once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Drug: Tivantinib; Tivantinib tablets; Other Names: ARQ197
Placebo Comparator: Placebo Matching 240 mg BID Cohort; Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.	Drug: Placebo; Matching placebo tablets; Other Names: Placebo comparator
Placebo Comparator: Placebo Matching 120 mg BID Cohort; Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.	Drug: Placebo; Matching placebo tablets; Other Names: Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Overall Survival (OS) Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy	Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.	within 36 months
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy	Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.	within 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy (ITT Population)	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause. The rate of PFS (percentage of participants still alive without disease progression) was determined only in the tivantinib 120 mg BID cohort.	within 10 months
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy	Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 120 mg BID cohort group.	Baseline to 30 days after last dose, up to approximately 4 years
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy	Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 240 mg BID cohort group.	Baseline to 30 days after last dose, up to approximately 4 years

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Publications and helpful links

General Publications

• Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, Lopez Lopez C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018 May;19(5):682-693. doi: 10.1016/S1470-2045(18)30146-3. Epub 2018 Apr 3.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2012
• Primary Completion (Actual): March 28, 2017
• Study Completion (Actual): July 31, 2017

Study Registration Dates

• First Submitted: December 19, 2012
• First Submitted That Met QC Criteria: December 19, 2012
• First Posted (Estimate): December 24, 2012

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Carcinoma; Unresectable; Hepatocellular; c-Met inhibitor; MET diagnostic-high
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: ARQ197-A-U303; 2012-003308-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO